Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes

Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum's dense dopaminergic innervation. Here, we...

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Bibliographic Details
Published in:Nature neuroscience 2022-11, Vol.25 (11), p.1559-1568
Main Authors: Benjamin, Kynon J M, Chen, Qiang, Jaffe, Andrew E, Stolz, Joshua M, Collado-Torres, Leonardo, Huuki-Myers, Louise A, Burke, Emily E, Arora, Ria, Feltrin, Arthur S, Barbosa, André Rocha, Radulescu, Eugenia, Pergola, Giulio, Shin, Joo Heon, Ulrich, William S, Deep-Soboslay, Amy, Tao, Ran, Hyde, Thomas M, Kleinman, Joel E, Erwin, Jennifer A, Weinberger, Daniel R, Paquola, Apuã C M
Format: Article
Language:English
Subjects:
Antipsychotic Agents - pharmacology
Antipsychotic Agents - therapeutic use
Antipsychotics
Bipolar disorder
Caudate Nucleus
Dopamine
Dopamine D2 receptors
Drug development
Gene expression
Gene mapping
Genes
Genetic analysis
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Innervation
Mental disorders
Neostriatum
Psychotropic drugs
Quantitative trait loci
Risk analysis
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - genetics
Schizophrenia - metabolism
Therapeutic targets
Transcriptome
Transcriptomes
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Summary:Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum's dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.
ISSN:1097-6256
1546-1726
DOI:10.1038/s41593-022-01182-7